In one aspect, this invention relates to neuroprotective and neuroregenerative compositions and derivatives and analogs thereof. More specifically, the invention relates to actinomycete strains for production of the neuroprotective and neuroregenerative compositions, pharmaceutical compositions containing the neuroprotective and neuroregenerative compositions and analogs, methods of making the neuroprotective and neuroregenerative compositions and methods of use thereof.
Immunophilins are proteins found in the immune systems and nervous systems of various cell types, e.g., bacteria, yeast, and a number of different types of mammalian cells. Classes of immunophilins include cyclophilins and FK506-binding proteins (e.g., FKBPs). Cyclosporin A is a macrolide immunophilin ligand that binds to cyclophilins. Other macrolide immunophilin ligands, such as meridamycin, FK506, and rapamycin, are understood to bind to FKBPs.
One way to describe intracellular functions of immunophilins is by identification of their enzymatic activity. Functions of FKBPs, for example, can be described in terms of their rotamase (i.e., petidy-prolyl cis-trans isomerase) activity.
FK506 and rapamycin are immunosuppressive immunophilin ligands. Meridamycin, on the other hand, is non-immunosuppressive. Salituro, et al., Tetrahedron Letters, Vol. 36, No. 7, 997–1000 (1995). In fact, meridamycin is an antagonist of both FK506 and rapamycin. (WO 94/18207).
Other non-immunosuppressive immunophilins are described by Steiner et al. (U.S. Pat. No. 6,500,843) who discuss using neurotrophic pipecolic acid derivative compounds having an affinity for FKBP-type immunophilins as inhibitors of the enzyme activity associated with immunophilin proteins, and particularly inhibitors of peptidyl-prolyl isomerase or rotamase enzyme activity to stimulate or promote neuronal growth or regeneration.
Meridamycin has been identified for uses such as an antidote for an overdose of macrophilin-binding-immunosuppressants such as FK506 or rapamycin, a steroid potentiator, and/or an anti-infective agent for infections or infectious diseases caused by organisms producing MIP (macrophage infectivity potentiator) or Mip-like factors. (WO 94/18207). In addition, meridamycin may be useful in the treatment of inflammatory/hyperproliferative skin diseases. (WO 94/18207).
It is desirable to find compounds that are neurotrophic, e.g., neuroprotective and/or neuroregenerative. A need exists in the art to provide compounds, and therapeutic drugs comprising such compounds.